The overall objective of this pilot project is to determine whether transgenic mouse lines expressing various human and bovine growth hormone (GH) genes may serve as a model system for studies of the neuroendocrine determinants of susceptibility to ethanol dependence. The rationale for the proposed studies is based on the observation that transgenic mouse lines under investigation in this laboratory differ significantly in the metabolism of forebrain dopamine, a substrate which has been implicated in substance abuse in humans, including alcohol dependence. Of particular interest is to observation of opposite effects of different GH genes on hypothalamic dopamine transmission. The proposed research project encompasses three specific aims: (1) To determine whether transgenic mouse lines expressing various GH genes and differing in dopaminergic function differ in ethanol self-administration and in the plasma levels of ethanol they obtain in a two-bottle choice situation; (2) to determine whether these mouse lines also differ in dopamine agonist-induced locomotor activity; and (3) to assess the degree to which susceptibility to ethanol self-administration in these mouse lines is related to dopamine agonist-induced locomotor activity. If transgenic mouse lines differ in these behaviors as expected, this will constitute evidence supporting the hypothesis that genetically altered central dopaminergic function contributes to susceptibility to ethanol self- administration. Furthermore, it will provide the basis for future studies of the involvement of forebrain dopaminergic systems in ethanol dependence using transgenic mice as a model system. These studies will include neuropharmacological experiments to identify cause-effect relationships between changes in dopaminergic activity and behavior, as well as site-directed in vitro mutagenesis to identify specific features of the GH gene and GH molecule that are responsible for the observed effects.